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108


Antibody-mediated enzyme formation: Its legacy at age fifty-four

Strom, Roberto; Celada, Franco
Antibody-mediated enzyme formation is a phenomenon first described in 1968 and further studied by molecular Immunologists and Biochemists over the following five decades. The present review is made mainly by analyzing the 27 articles concerned with AMEF that appeared over the course of 47 years, commenting 16 original figures selected to be re-printed in AMEF's Legacy. We, the reviewers, started by revisiting our own "insider's" experience of discovery, and followed by considering all results, our own and of members of other AMEF Labs. We had planned to conclude the review by correlating the various AMEF mutants to a detailed knowledge of the consensus betaGal structure. However, we became aware of several "robust" papers, published between 1989 and 2014, by authors outside of AMEF Labs. We familiarly called this surge: "The Second Wave" and adorned it with a doodle in Hokusai style. We were thrilled and happy to take them on board and properly examined their data. A team of this second wave had imagined unique uses for AMEF, and new doors to modern biotechnology. Another one had used AMEF as Tool and Marker to attain high levels of crystallography, solving puzzles of conformation, and ultimate structure. Together, they doubled our motivation to review AMEF. Serendipity gives us back the pleasure of finding, a treat at any age.
PMID: 34693572
ISSN: 1099-1352
CID: 5042222

Homage to Eli Sercarz

Celada, Franco
SCOPUS:85097500763
ISSN: 1040-8401
CID: 4733432

Computer Modeling of Clonal Dominance: Memory-Anti-Naïve and Its Curbing by Attrition

Castiglione, Filippo; Ghersi, Dario; Celada, Franco
Experimental and computational studies have revealed that T-cell cross-reactivity is a widespread phenomenon that can either be advantageous or detrimental to the host. In particular, detrimental effects can occur whenever the clonal dominance of memory cells is not justified by their infection-clearing capacity. Using an agent-based model of the immune system, we recently predicted the "memory anti-naïve" phenomenon, which occurs when the secondary challenge is similar but not identical to the primary stimulation. In this case, the pre-existing memory cells formed during the primary infection may be rapidly deployed in spite of their low affinity and can actually prevent a potentially higher affinity naïve response from emerging, resulting in impaired viral clearance. This finding allowed us to propose a mechanistic explanation for the concept of "antigenic sin" originally described in the context of the humoral response. However, the fact that antigenic sin is a relatively rare occurrence suggests the existence of evolutionary mechanisms that can mitigate the effect of the memory anti-naïve phenomenon. In this study we use computer modeling to further elucidate clonal dominance and the memory anti-naïve phenomenon, and to investigate a possible mitigating factor called attrition. Attrition has been described in the experimental and computational literature as a combination of competition for space and apoptosis of lymphocytes via type-I interferon in the early stages of a viral infection. This study systematically explores the relationship between clonal dominance and the mechanism of attrition. Our results suggest that attrition can indeed mitigate the memory anti-naïve effect by enabling the emergence of a diverse, higher affinity naïve response against the secondary challenge. In conclusion, modeling attrition allows us to shed light on the nature of clonal interaction and dominance.
PMCID:6626922
PMID: 31338096
ISSN: 1664-3224
CID: 3987142

Heterologous immunity: immunopathology, autoimmunity and protection during viral infections

Selin, Liisa K; Wlodarczyk, Myriam F; Kraft, Anke R; Nie, Siwei; Kenney, Laurie L; Puzone, Roberto; Celada, Franco
Heterologous immunity is a common phenomenon present in all infections. Most of the time it is beneficial, mediating protective immunity, but in some individuals that have the wrong crossreactive response it leads to a cascade of events that result in severe immunopathology. Infections have been associated with autoimmune diseases such as diabetes, multiple sclerosis and lupus erythematosis, but also with unusual autoimmune like pathologies where the immune system appears dysregulated, such as, sarcoidosis, colitis, panniculitis, bronchiolitis obliterans, infectious mononucleosis and even chronic fatigue syndrome. Here we review the evidence that to better understand these autoreactive pathologies it requires an evaluation of how T cells are regulated and evolve during sequential infections with different pathogens under the influence of heterologous immunity
PMCID:3633594
PMID: 21250837
ISSN: 1607-842x
CID: 133356

Systematic simulation of cross-reactivity predicts ambiguity in Tk memory: It may save lives of the infected, but limits specificities vital for further responses

Pearson, Yanthe E; Cheng, Yiming; Selin, Liisa K; Puzone, Roberto; Celada, Franco
The present study uses the agent-based model IMMSIM to simulate immune responses to a viral infection, with a focus on the impact of preformed memory (homologous and heterologous) on the quality and the efficacy of the response. The in machina results confirm the observed thwarting of new, naive responses exerted by cross-reacting memory, but they also reveal that the competitive inhibition is made possible by the different time frame used by the primary and the secondary response, a well-known fact, epitomized by the interval of about 75 time steps between their peaks. This novel finding justifies the depression of naive responses and the long-term consequences it could bring about and the role of memory as a player in a survival of the fittest game
PMCID:3703517
PMID: 21231890
ISSN: 1607-842x
CID: 130901

Introduction: Knowledge is survival-The mission of the immune system and its stochastic simulations

Celada, Franco
In this introduction the timeliness and interest of dedicating an issue of Autoimmunity to mostly 'discrete' models is motivated by highlighting number of circumstances, observations encounters, that all have favored the rise of a family of agent based simulations of the Immune System. Franco Celada was among the first experimentalists to accept the challenge of interdisciplinarity and create a computational Immune System. He thinks that discrete models are especially useful in handling hypotheses: initiating them, representing their consequences, and revealing their plusses and minuses. He is sure that 'looking at' the immune machinery as a cognitive system is useful both to the intuitive understanding and the creative development of models
PMID: 21271820
ISSN: 1607-842x
CID: 130904

Computer simulations of heterologous immunity: Highlights of an interdisciplinary cooperation

Calcagno, Claudia; Puzone, Roberto; Pearson, Yanthe E; Cheng, Yiming; Ghersi, Dario; Selin, Liisa K; Welsh, Raymond M; Celada, Franco
The relationship between biological research and mathematical modeling is complex, critical, and vital. In this review, we summarize the results of the collaboration between two laboratories, exploring the interaction between mathematical modeling and wet-lab immunology. During this collaboration several aspects of the immune defence against viral infections were investigated, focusing primarily on the subject of heterologous immunity. In this manuscript, we emphasize the topics where computational simulations were applied in conjunction with experiments, such as immune attrition, the growing and shrinking of cross-reactive T cell repertoires following repeated infections, the short and long-term effects of cross-reactive immunological memory, and the factors influencing the appearance of new clonal specificities. For each topic, we describe how the mathematical model used was adapted to answer specific biological questions, and we discuss the hypotheses that were generated by simulations. Finally, we propose rules for testing hypotheses that emerge from model experimentation in the wet lab, and vice-versa
PMCID:3633596
PMID: 21271821
ISSN: 1607-842x
CID: 130905

The anti-DNA story

Celada, F
PMID: 21183564
ISSN: 1477-0962
CID: 132308

Broad cross-reactive TCR repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes

Clute, Shalyn C; Naumov, Yuri N; Watkin, Levi B; Aslan, Nuray; Sullivan, John L; Thorley-Lawson, David A; Luzuriaga, Katherine; Welsh, Raymond M; Puzone, Roberto; Celada, Franco; Selin, Liisa K
Memory T cells cross-reactive with epitopes encoded by related or even unrelated viruses may alter the immune response and pathogenesis of infection by a process known as heterologous immunity. Because a challenge virus epitope may react with only a subset of the T cell repertoire in a cross-reactive epitope-specific memory pool, the vigorous cross-reactive response may be narrowly focused, or oligoclonal. We show in this article, by examining human T cell cross-reactivity between the HLA-A2-restricted influenza A virus-encoded M1(58-66) epitope (GILGFVFTL) and the dissimilar Epstein-Barr virus-encoded BMLF1(280-288) epitope (GLCTLVAML), that, under some conditions, heterologous immunity can lead to a significant broadening, rather than a narrowing, of the TCR repertoire. We suggest that dissimilar cross-reactive epitopes might generate a broad, rather than a narrow, T cell repertoire if there is a lack of dominant high-affinity clones; this hypothesis is supported by computer simulation
PMCID:3738202
PMID: 21048112
ISSN: 1550-6606
CID: 138027

A discrete computer model of the immune system reveals competitive interactions between the humoral and cellular branch and between cross-reacting memory and naive responses

Cheng, Yiming; Ghersi, Dario; Calcagno, Claudia; Selin, Liisa K; Puzone, Roberto; Celada, Franco
In an agent-based computer model, we simulate the formation and recall of anti-virus immunological memory. Specifically we try to predict what will happen, both to the response and to memory, when the second infecting virus is partly different from the first one, and when the cross-reactivity of the two branches of the immune system (IS), humoral and cellular, is asymmetrical, or 'split'. The simulations explore systematically epitope distances, and measure all changes in affinity, cellularity and efficiency in clearing the infection. Besides obvious cooperation, they reveal powerful competitions between the branches, and more intriguing, between cross-reacting and new responses when the latter suffer the competition by preformed cell-rich but inefficient clones, as memory, usually an asset, becomes a liability
PMCID:3905836
PMID: 19101600
ISSN: 0264-410x
CID: 95964